The hypothesis that the symptoms of neurodegenerative diseases such as Alzheimer's Disease are the result of reduced neuronal function has led to the development of therapies aimed at reversing these deficits. In an attempt at neurotransmitter replacement, neurotransmitter precursor supplementation has been used to treat neurodegenerative diseases. Cotzias, et al. New Engl. J. Med. 276:374-379 (1967).
Another means of enhancing neurotransmission is to increase stimulated, but not basal, release of neurotransmitters, thereby specifically increasing normal synaptic activity. Substituted oxindoles such as 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one are agents under investigation as a palliative treatment for the dementia associated with Alzheimer's disease. Compounds of this structural type have been shown to enhance potassium(K.sup.+)-stimulated release of tritium from rat brain slices preloaded with [.sup.3 H]choline, [.sup.3 H]dopamine, and [.sup.3 H]serotonin without affecting basal efflux. Nickolson et al., Drug Dev. Res. 19:285-300 (1990); Zaczek et al. Neurosci. Lett. (1993); Zaczek et al., Drug Dev. Res. 29:203-208 (1993).
The present invention is based on a synergy found with a combination therapy involving neurotransmitter release enhancers, and acetylcholinesterase inhibitors. Such a therapy provides higher extracellular levels of acetylcholine and a greater improvement for the treatment of neurological disorders such as Alzheimer's disease.